L-DON

Abstract

Abnormal metabolism is another cancer hallmark. The two most characterized altered metabolic pathways are high rates of glycolysis and glutaminolysis, which are natural targets for cancer therapy. Currently, a number of newer compounds to block glycolysis and glutaminolysis are being developed; nevertheless, lonidamine and 6-diazo-5-oxo-L-norleucine (DON) are two old drugs well characterized as inhibitors of glycolysis and glutaminolysis, respectively, whose clinical development was abandoned years ago when the importance of cancer metabolism was not fully appreciated and clinical trial methodology was less developed. In this review, a PubMed search using the words lonidamine and 6-diazo-5-oxo-L-norleucine (DON) was undertaken to analyse existing information on the preclinical and clinical studies of these drugs for cancer treatment. Data show that they exhibit antitumor effects; besides there is also the suggestion that they are synergistic. We conclude that lonidamine and DON are safe and potentially effective drugs that need to be reevaluated in combination as metabolic therapy of cancer.

2. Glycolytic and Glutaminolytic Inhibitors in Development

Regarding glutaminolytic agents, these are fewer. Among these oldest ones are the (i) glutamine analogs: acivicin, 6-diazo-5-oxo-L-norleucine (DON), azaserine, and azotomycin and (ii) miscellaneous more selective and potent inhibitors: bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) and its analogs. Other agents are ebselen, chelerythrine, apomorphine, and CB-839 [–]. Apart from the oldest analogs of glutamine such as acivicin, DON, azaserine, and azotomycin which were clinically evaluated several decades ago and their development abandoned, only CB-839 among the newest analogs has recently reached to phase I clinical trials.

4.1. Chemistry

6-Diazo-5-oxo-L-norleucine also known as DON was initially described as an antitumor antibiotic isolated from an unidentified streptomyces strain. It has a molecular weight of 171.15 and its empirical formula is C6H9N3O3. DON is very sensitive to heat and pH, and the optimal pH at room temperature ranges from 4.5 to 6.5. DON is a light yellow powder very soluble in water and aqueous solutions of methanol, acetone, or ethanol []. As an analog of glutamine, DON has been used as an inhibitor of glutamine utilizing enzymes such as carbamoyl phosphate synthase (CAD), CTP synthase (CTPS), FGAR amidotransferase, guanosine monophosphate synthetase (GMPS), PRPP amidotransferase, NAD synthase, asparagine synthase, and glutaminase. These enzymes are used in several important metabolic pathways such as the purine, pyrimidine, and amino acid synthesis as well as a coenzyme of the electron transport chain and in the first step of glutaminolysis [–].

4.5. Safety and Tolerability

From the experience with DON for cancer treatment it can be concluded that it is a safe drug and that the dose-limiting toxicity is nausea and vomiting which varied according to the schedule and dose. Divided doses (every four or six hours) caused more nausea and vomiting than the same dose in single daily administration. Despite the fact that DON in addition to its inhibitory action upon GSL1 has a number of targets involved in DNA synthesis, the resulting myelotoxicity is mild with fast recovery, manifested by leucopenia and thrombocytopenia and never life threatening.